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Regulation of myeloid leukemia by the cell fate determinant Musashi

Chronic myelogenous leukemia (CML) can progress from an indolent chronic phase to an aggressive blast crisis phase1 but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML2,3 to show that disease progression is regulated by the Musashi-Numb signali...

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Detalles Bibliográficos
Autores principales: Ito, Takahiro, Kwon, Hyog Young, Zimdahl, Bryan, Congdon, Kendra L., Blum, Jordan, Lento, William E., Zhao, Chen, Lagoo, Anand, Gerrard, Gareth, Foroni, Letizia, Goldman, John, Goh, Harriet, Kim, Soo-Hyun, Kim, Dong-Wook, Chuah, Charles, Oehler, Vivian G., Radich, Jerald P., Jordan, Craig T., Reya, Tannishtha
Formato: Texto
Lenguaje:English
Publicado: 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918284/
https://www.ncbi.nlm.nih.gov/pubmed/20639863
http://dx.doi.org/10.1038/nature09171
Descripción
Sumario:Chronic myelogenous leukemia (CML) can progress from an indolent chronic phase to an aggressive blast crisis phase1 but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML2,3 to show that disease progression is regulated by the Musashi-Numb signaling axis4,5. Specifically, we find that chronic phase is marked by high and blast crisis phase by low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced phase disease in vivo. As a possible explanation for the decreased levels of Numb in blast crisis, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML6,7, can trigger expression of the RNA binding protein Musashi2 (Msi2) which in turn represses Numb. Importantly, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally, we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for therapy of aggressive leukemias.